Absolute requirement for iron in the development of chemically induced uroporphyria in mice treated with 3-methylcholanthrene and 5-aminolevulinate.
Accumulating evidence, including experiments using cytochrome P450 1a2 (Cyp1a2) gene knock-out mice (Cyp1a2(-/-)), indicates that the development of chemically induced porphyria requires the expression of CYP1A2. It has also been demonstrated that iron enhances and expedites the development of experimental uroporphyria, but that iron alone without CYP1A2 expression, as in Cyp1a2(-/-) mice, does not cause uroporphyria. The role of iron in the development of porphyria has not been elucidated. We examined the in vivo effect of iron deficiency on hepatic URO accumulation in experimental porphyria. Mice were fed diets containing low (iron-deficient diet (IDD), 8.5 mg iron/kg) or normal (normal diet (ND), 213.7 mg iron/kg) levels of iron. They were treated with 3-methylcholanthrene (MC), an archetypal inducer of CYP1A, and 5-aminolevulinate (ALA), precursors of porphyrin and heme. We found that uroporphyrin (URO) levels and uroporphyrinogen oxidation (UROX) activity were markedly increased in ND mice treated with MC and ALA, while the levels were not raised in IDD mice with the same treatments. CYP1A2 levels and methoxyresorufin O-demethylase (MROD) activities, the CYP1A2-mediated reaction, were markedly induced in the livers of both ND and IDD mice treated with MC and ALA. UROX activity, supposedly a CYP1A2-dependent activity, was not enhanced in iron-deficient mice in spite of the fact of induction of CYP1A2. We showed that a sufficient level of iron is essential for the development of porphyria and UROX activity.
Nakano
Kenzi
K
Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo, 060-0818, Japan.
Ishizuka
Mayumi
M
Sakamoto
Kentaro Q
KQ
Fujita
Shoichi
S
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000737:chemistry; D011164:Porphyrias / Q000139:chemically induced* / Q000378:metabolism; D013997:Time Factors; D014577:Uroporphyrinogens / Q000737:chemistry / Q000378:metabolism; D014578:Uroporphyrins / Q000737:chemistry / Q000378:metabolism*
D014577:Uroporphyrinogens; D014578:Uroporphyrins; D008748:Methylcholanthrene; C034103:uroporphyrin I; D000622:Aminolevulinic Acid; D007501:Iron; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D010100:Oxygen